The present invention, in some embodiments thereof, relates to methods of using PEDF for the treatment and prevention of agent-induced gonadal or uterine toxicity.
Over the past three decades, there has been a remarkable improvement in the survival rates of cancer patients owing to progress in earlier stage diagnosis and improvements in treatment. As a consequence, greater attention has been focused on the delayed effects of cancer treatments on the life quality of healed subjects.
The treatment for most cancer types involves cytotoxic treatments such as chemotherapy and radiotherapy that may partially or definitively affect the reproductive function, hinder the hormonal milieu and gonadal reserve, and may subsequently induce either sterility or early menopause. The risk of gonadal and uterine toxicity following cancer therapy appears to be treatment and dose-dependent and age related. Thus, for example the use of Tamoxifen as an antagonist to estrogen receptor for the treatment of breast cancer, for example, results in an agonistic activity in the uterus that results in a range of endometrial pathologies including hyperplasia and endometrial cancer (Obstet Gynecol. 2014 June; 123(6):1394-7). Some of the chemotherapeutic agents e.g., doxorubicin (DXR), cyclophosphamide, busulfan and ifosfamide, which are frequently used for the treatment of various cancers including breast cancer, lymphomas, leukemia and sarcomas, are known to have irreversible gonadotoxic effects. Gonadal dysfunction following radiotherapy may occur when the gonads are close to or within the radiation field [Brydøy et al. Acta Oncologica (2007). 46: 480-489].
Gonadal dysfunction following cancer treatment has been attributed both to induction of vascular damage leading to ischemia and to direct acute insult to the gonads by apoptosis induction such as by induction of oxidative stress and increase in intracellular calcium [Ben-Aharon et al., Reprod Biol Endocrinol (2010), 8:20; Kampfer et al. Life Sci. (2014) 97(2): 129-36; Bar-Josef et a. Reproductive Toxicology (2010), 30: 566-572; and Bar-Joseph et al. PLoS One (2011) 6: e23492].
Strategies aiming to preserve fertility in patients with different types of malignancies include in-vitro fertilization (IVF), embryo, oocyte and semen cryopreservation, cortical and whole ovary cryopreservation, ovarian transplantation, ovarian transposition, and GnRH agonist protection. To date, embryo and mature oocyte cryopreservation following IVF are the only techniques endorsed by the American Society of Reproductive Medicine.
Pigment epithelium-derived factor (PEDF) is a non-inhibitory member of the serine protease inhibitors (serpin) superfamily, which was first described as a neurotrophic factor, able to promote and support the growth of neuronal cells. It was later found that on top of having neurotrophic activity, PEDF has an anti-angiogenic, anti-inflammatory and anti-oxidative properties. To date, two distinct PEDF receptors were proposed: an 80 kDa PEDF putative receptor (PEDF-RN; PNPLA2) involved in PEDF neuroprotecting, pro-survival functions; and a 60 kDa PEDF putative receptor (PEDF-RA; Laminin receptor) involved in PEDF pro-apoptotic, anti-angiogenic activities [Manalo et al. Expert Opin Ther Pat (2011): 21, 121-130; and Yamagishi et al. Cell Tissue Res (2005) 320: 437-445]. Although originally discovered in culture media of retinal pigment epithelial cells, PEDF is widely expressed throughout the body: the nervous system, ovary, uterine, liver and plasma. Despite the significant expression of PEDF in the reproductive system, there is only limited data about its function in the ovary and uterus [Cheung et al., Endocrinology, 2006. 147(9): p. 4179-91; Chuderland et al. J Clin Endocrinol Metab (2013) 98: E258-266; and Chuderland et al. Mol Hum Reprod (2013) 19: 72-81; Pollina et al., Cell Cycle, 2008. 7(13): p. 2056-70; Palmieri et al. Exp Cell Res, 1999. 247(1): p. 142-7.]. Previous work has suggested using PEDF in the treatment of tumors mainly due to its anti-angiogenic effect [Manalo et al. Expert Opin Ther Pat (2011): 21, 121-130].
Additional Related Background Art:    U.S. Patent Publication Number US20130053312.    U.S. Patent Publication Number US20030216286.    U.S. Patent Publication Number US20070087967.    U.S. Patent Publication Number US20040071659.    U.S. Patent Publication Number US20090118191.    Nelius et al. [J Clin Oncol 31, 2013 (suppl 6; abstr 173)].    Choong et al. [The Liddy Shriver Sarcoma Initiative—PEDF: A Potential Therapeutic Agent for Osteosarcoma: sarcomahelpdotorg/research/osteosarcoma-pedfdothtml].    Ma and Waxman [Mol Cancer Ther. (2008) 7(12): 3670-3684].    Jia and Waxman [Cancer Lett. (2013) 330(2):241-9].